Genetic Dissection of Serotonergic Phenotypes in C. elegans

描述（由申请人提供）：在脊椎动物和无脊椎动物中，血清素（5HT）信号调节大量的行为和生理过程。5HT表型复杂性的遗传基础和分子机制尚不清楚。因此，阐明调控5HT神经元发育和功能的基因和分子机制将有助于深入了解神经元多样性的原理，并揭示神经系统和生理在分子和细胞水平上的相互作用。利用复杂的秀丽隐杆线虫遗传学、我们独特的突变体和分子标记，我们可以在活体动物的单细胞分辨率下定量测量5HT的产生，我们正在对5HT系统进行遗传解剖，测试一个中心假设：不同神经元中5HT的产生受不同转录因子的调控，受到不同机制的调节，以响应不同的内外环境刺激，服务于不同的生理功能。这项建议有四个具体目标。(1)通过我们收集的突变体的基因定位和rna干扰筛选，我们将定义指定5HT身份的新基因，并在已鉴定的神经元中调节5HT的产生。(2)利用抑制基因，我们将遵循我们的发现，即一对5HT神经元的感觉末端的TRP通道通过定义与通道相互作用和作用于通道下游的成分来控制5HT的产生。(3)利用分子、细胞和行为方法，我们将把已识别的基因组织成分子和细胞途径。(4)利用我们已建立的范例，我们将测试特定5HT神经元中的特定信号级联是否调节特定行为，以及它们是否控制不同的应激反应途径。针对5HT系统的药物是治疗抑郁症和许多行为和神经精神疾病最常用的处方疗法。对模式生物中调节5HT信号的基因和生化途径的识别，将导致令人信服的新候选物在与疾病的关联研究中进行测试，可能导致新的诊断和新的药物。

DESCRIPTION (provided by applicant): In both vertebrates and invertebrates, serotonin (5HT) signaling regulates a vast array of behavior and physiological processes. The genetic basis and molecular mechanisms underlying the complexity of 5HT phenotypes are not well understood. Thus elucidation of genes and molecular mechanisms that regulate the development and function of 5HT neurons will provide insights into the principles of neuronal diversity and reveal reciprocal effects of the nervous system and physiology at molecular and cellular levels. Taking the advantage of sophisticated C. elegans genetics, our unique mutants, and molecular markers that allow a quantifiable measure of 5HT production at the resolution of single cells in living animals, we are undertaking genetic dissection of the 5HT system, testing a central hypothesis: 5HT production in different neurons is regulated by different transcription factors and is modulated by different mechanisms in response to different internal and external environmental stimuli to subserve different physiological functions. This proposal has four specific objectives. (1) By genetic mapping of our collected mutants and RNA-interference screens, we will define new genes that specify 5HT identity and that regulate 5HT production in identified neurons. (2) Using suppressor genetics, we will follow our discovery that a TRP channel at the sensory ending of a pair of 5HT neurons controls 5HT production by defining components that interact with and that act downstream of the channel. (3) Using molecular, cellular, and behavioral approaches, we will organize so identified genes into molecular and cellular pathways. (4) Using our established paradigms, we will test whether specific signaling cascades in specific 5HT neurons modulate specific behavior and if they control distinct stress responsive pathways. Drugs that target the 5HT system are the most commonly prescribed therapeutics for the treatment of depression and many behavioral and neuropsychiatric disorders. Identification of genes and biochemical pathways that regulate 5HT signaling in a model organism will lead to compelling new candidates to be tested in association studies with the diseases, potentially leading to novel diagnostics and new medications.